Experts Remark on CAR T-Cell Therapy at 1-Year Milestone, Where It Is Headed

Chimeric antigen receptor (CAR) T-cell therapy recently reached its 1-year milestone after the FDA approval of tisagenlecleucel (Kymriah), a CD19-directed CAR T-cell product for the treatment of patients up to 25 years of age with B-cell acute lymphoblastic leukemia, based on the ELIANA study in August 2017.¹

Since then, the indication for tisagenlecleucel has been expanded by the FDA to include adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and another CAR T-cell therapy has been granted an approval for patients in a similar setting.

“What’s very exciting [about the potency of CAR T-cell therapy] is not just the responses but the durability of responses…which may represent cure for some patients,” said Ran Reshef, MD, MSc.

With 2 CAR T-cell therapies now approved and more moving quickly through early-phase clinical trials, 4 healthcare experts reflected on the evolving field of CAR T-cell therapy, their understanding of its current and future applicability for patients, the process for administration and the challenges and obstacles that remain unaddressed during an Association of Community Cancer Centers interactive panel.

Current and Future CAR T-Cell Agents

There have been 2 FDA approvals for CD19-targeting CAR T-cell therapy in the past year. Axicabtagene ciloleucel (axi-cel; Yescarta) was approved for patients with relapsed/refractory DLBCL based on findings from the phase II ZUMA-1 study.²The best objective response rate (ORR) achieved with the therapy was 82%, and the best complete response (CR) rate was 54%. At a follow-up of 12 months, the durable ORR was 42% and the durable CR was 40%.

“These are considered [to be] challenging patients who generally fail to respond to subsequent lines of therapy,” added Reshef, director of translational research, blood and marrow transplantation, Columbia University Medical Center.

Shortly thereafter, in May 2018, tisagenlecleucel received another indication to join axi-cel as the second CAR T-cell therapy for patients with DLBCL. Based on updated findings from the phase II JULIET study, the best ORR was 52% and the best CR rate was 40%.³

“In addition to the approved products, just to indicate that the field is far from being at a standstill, there are [currently] more than 400 clinical trials using CAR T cells around the world,” said Reshef.

Lisocabtagene maraleucel (liso-cel; JCAR017) now shows promise to become the third CD19-targeting CAR T-cell therapy for patients with relapsed/ refractory DLBCL. In the phase II TRANSCEND study, the best ORR was 80% and the best CR rate was 59%. At a 6-month follow-up, the durable ORR was 47% and the durable CR rate was 41%.⁴

Other targets are currently being explored in B-cell malignancies, Reshef continued, including B-cell maturation antigen (BCMA), CD20, CB22, and CD123. In the phase I CRB-401 study, the anti- BCMA CAR T-cell therapy bb2121 induced an ORR of 95.5% and a CR of 50.0% with a dose >150 x 10⁶for patients with relapsed/refractory heavily pretreated multiple myeloma.5 In contrast, those treated with an inactive dose of 5 x 10⁶had an ORR of 33.3% and a 1.9-month duration of response (DOR).

Reshef also referenced CAR T-cell combination therapy, including anti-CD19 CAR T-cell therapy in combination with ibrutinib (Imbruvica) for patients with high-risk chronic lymphocytic leukemia who did not obtain a CR despite 6 months of ibrutinib (NCT02640209).

Patient Selection

The logistics in identifying the appropriate candidates for these CAR T-cell therapies continue to develop, explained Murali Janakiram, MD, assistant professor of medicine, Montefiore Medical Center, Albert Einstein College of Medicine. In the Department of Bone Marrow Transplant, weekly meetings are held to discuss all relapsed/ refractory lymphoma cases. Tumor boards, he added, are another resource used to identify CAR T-cell referrals. “We participate in tumor boards at different community hospitals, and we get referrals from [those boards].”

Although early predictors of response remain somewhat unknown, Reshef specified certain subgroup characteristics where responses have been noted.

In a retrospective analysis of the ZUMA-1 study, patients who received 1 to 2 lines of therapy prior to CAR T-cell therapy achieved an ORR of 91%.⁶The ORR sharply declined, however, for those who received more than 5 lines of therapy to 38%. The analysis also showed a better ongoing response at 1 year for those who received fewer lines of therapy.

Disease burden also seems to play a role in patient selection, according to Reshef. Although the analysis demonstrated a relatively consistent ORR across the disease burden subgroup, the DOR was less for those who had a higher disease burden after 1 year (27% vs 67%, respectively).

“We shouldn’t wait until patients have exhausted every possible line of therapy,” he said. “We want to catch them at the point where we can still reduce the burden of disease with chemotherapy.”

In an informal poll of the webinar audience, it was found that none of the physicians had referred a patient to CAR T-cell therapy within the previous month. This is a current barrier and patients should be referred much sooner once they are selected as candidates, said Karen G. Wright, MS, RN-BC, OCN, BMTCN.

“The longer we wait to refer this patient to [CAR T-cell therapy], the harder it is for the patient to respond,” said Wright, Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine.

Toxicities and Management

The goal of managing toxicity associated with CAR T-cell therapy is to minimize a life-threatening complication while maximizing the effect of therapy, according to Elsa M. Delille, MSN, FNP-BC.

This requires a cell therapy program that can recognize signs of potential decompensation from the patient early on. “It is a multidisciplinary approach, including ICU, pharmacy, and the infusion center. Everyone is involved…including nononcology personnel,” said Delille, Blood and Marrow Transplantation Program, Columbia University Medical Center.

“We are all used to chemotherapy and immunotherapy by now, and we know the [AEs]—we are familiar with them,” she said. “But I think with CAR T-cell therapy, we are actually dealing with a whole different world, and it is a completely different beast.”

Cytokine release syndrome (CRS) is observed to be the most common AE seen in clinical trials involving CAR T-cell therapy and can exist on a wide spectrum, from mild to severe, she said. The rapid release of cytokines into the bloodstream can lead to high fevers and low blood pressures in severe cases. To manage these symptoms, tocilizumab (Actemra)—an IL-6 receptor antagonist—was approved by the FDA in August 2017.

Other commonly documented AEs include nontoxicity, cytopenia, and prolonged hypogammaglobulinemia due to B-cell aplasia. All these symptoms, however, are reversible, according to Delille.

Toxicity from CAR T-cell therapy may occur within hours; however, the AEs generally appear within 1 to 14 days after infusion. This timeline coincides with maximal T-cell expansion. The median time to CRS onset is 2 to 3 days, while the median time to neurotoxicity onset is 4 to 6 days.

“After 8 weeks, toxicities are very rare,” Delille added. “We have not seen any in our practice and our patients are about 6 weeks out. Everyone should be excited about that because patients can remain in their hometown and be monitored by their primary oncologist.”

Currently, there are ongoing efforts dedicated toward decreasing toxicities and enabling better access for patients at nonacademic centers who don’t have access to sophisticated intensive care unit resources.

Ongoing Barriers

Another obstacle is the location of the treatment center. It takes a significant amount of capital to invest in a CAR T-cell therapy program, said Wright, and most of the centers that currently offer the therapy are academic centers that already had a stable blood and marrow transplant program. This can be difficult for patients, particularly those who are susceptible to quick relapse or progression, who are not near one of these centers.

“If we have a patient [far away] who is referred to us, by the time we can coordinate the logistics to get that patient into [our center] and get everything up and running, patients do relapse,” she explained.

Of all the continued obstacles seen for CAR T-cell therapy, financial costs and resources remain at the forefront. “The payment structure is the biggest barrier right now,” Wright said. Totaling upward of $500,000, CAR T-cell therapy expenses include ancillary care for hospitalization, observation, and treatment of adverse events (AEs).

Wright noted that most lymphodepletion and other conditioning regimens are currently administered in an inpatient setting, which leads to additional costs.

“In our facility, we are strapped for chair time,” she said. “We are admitting these patients for these lymphodepleting regimens that really could be done in an outpatient basis. This ends up costing us.”

It is unclear how CAR T-cell therapy costs should be covered, Wright added. Currently, the Centers for Medicare & Medicaid Services has offered to reimburse a set rate for CAR T-cell infusion, which does not cover the total costs involved in the procedure. This has prevented some academic centers from performing these infusions completely.

References:

1. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.N Engl J Med.2018;378(5):439-448. doi: 10.1056/NEJMoa1709866.
2. Locke FL, Neelapu SS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Presented at: 2017 American Association for Cancer Research Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT019.
3. Borchmann P, Tam CS, Jager U, et al. An updated analysis of JULIET, a global pivotal phase 2 trial of tisagenlecleucel in adult patients with relapsed or refractory (r/r) diffuse large b-cell lymphoma (DLBCL). Presented at: 2018 European Hematology Association Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S799.
4. Abramson JS, Gordon LI, Palomba ML, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL.J Clin Oncol.2018;36(suppl; abstr 7505). doi: 10.1200/JCO.2018.36.15_ suppl.7505.
5. Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/ refractory multiple myeloma: updated results from a multicenter phase I study.J Clin Oncol.2018;36(suppl; abstr 8007). doi: 10.1200/JCO.2018.36.15_suppl.8007.
6. Locke FL, Ghobadi A, Lekakis LK, et al. Outcomes by prior lines of therapy (LoT) in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory B-cell lymphoma.J Clin Oncol.2018;36(suppl; abstr 3039). meetinglibrary.asco.org/ record/159223/abstract.